Gonorrhea and chlamydia are the most common bacterial sexually transmitted infections worldwide and adversely impact the reproductive health of women. In addition to complications such as pelvic inflammatory disease and tubal scarring with consequent infertility or ectopic pregnancy, they enhance HIV transmission. Gonorrhea and chlamydia frequently exist as coinfections. The gonococcus has displayed a remarkable ability to become resistant to every antibiotic that it has encountered. The emergence of Neisseria gonorrhoeae (Ng) strains that are resistant to third-generation cephalosporins has heralded an era of untreatable gonorrhea. Vaccines and novel therapeutics against Ng are needed urgently. Our group has developed a gonococcal vaccine candidate that comprises a peptide mimic (a 'mimitope') of a Ng lipooligosaccharide epitope that is expressed by >95% of strains in vivo. This mimitope, when configured as a multi-antigen peptide vaccine, decreases Ng burden in the mouse vaginal colonization model. Based on our working knowledge of interactions of the complement (C) inhibitor factor H (fH) with Ng, we have fused the A/g-binding domains of fH to IgG Fc to create a novel immunotherapeutic, called fH/Fc. A point mutation introduced in the fH fragment of fH/Fc abrogated C'-mediated lysis of host cells, yet allowed fH/Fc to bind to, activate C on and kill drug-resistant Ng. Elucidating factors that facilitate Ng transmission and gaining a global understanding of host responses are critical for developing safe and effective vaccines and therapeutics against Ng. These studies are highly relevant in context of chlamydia coinfection, a commonly encountered clinical scenario, because chlamydia may subvert immunity to increase Ng burden that our vaccine and fH/Fc must overcome. We have observed that certain Ng strains are transmitted far less efficiently than other closely related Ng lineages. In Aim 1a we will compare the ability of low vs. high transmitted Ng to evade C, cationic peptides, and adhere to and invade human endocervical cells to better understand why strains differ in their transmissibility. Ongoing data analysis of Ng infected men and their female partners at the Nanjing, China, STD clinic site suggest that preexisting Chlamydia trachomatis (Ct) infection enhances the transmission of Ng from men to women. In Aim 1b we will define the role of Cf load and/or serovar in increasing Ng transmission. Mice infected with Cf suffer a greater burden of Ng infection. Global transcriptome analyses on mice infected with Ng, Ct or dual Ng/Ct coinfection will be performed in Aim 2a to elucidate how Cf subverts host defenses to enhance Ng infection; these data will be compared with human transcriptome data (Genco, Project 4). The ability of our mimitope Ng vaccine candidate to attenuate Ng in the mouse A/g/Cf coinfection model will be studied in Aim 2b. Aim 3a will evaluate the efficacy of fH/Fc in mice infected with drug-resistant Ng alone and Ng/Ct coinfection. In Aim 3b we will use mice that lack critical C components (C3, C5, C5a receptor) or effector arms of phagocytosis (e.g., PMNs, macrophages or Fc receptors) to elucidate the mechanism of action of fH/Fc in vivo.